Project summary/abstract Genetic changes over the last six million years have transformed the structure and function of the human brain. However, identifying the key genetic changes that transform developmental process has been challenging because developmental tissue is largely inaccessible to comparative and functional studies. This project will establish a systematic quantitative genetic approach for discovering the human-specific genomic changes that underlie unique features or vulnerabilities of the developing human brain. Our project leverages human and great ape pluripotent stem cell and cerebral organoid models that we have established to perform comparative analysis of gene activity and cell behavior during hominid cortical development. In addition, by incorporating advances in genome engineering screens and novel chromosome engineering strategies, this project will perform large-scale functional analysis of human-specific variants in the context of key processes of cortical development. Finally, this project involves the development of novel and generalizable tools for both the derivation of specific cell types from pluripotent stem cells across many individuals and species and for high-throughput analysis of cellular phenotypes. Ultimately, our vision of success will be a platform that enables a quantitative understanding of the extent to which individual human-specific mutations explain variation in specialized aspects of human brain development.